Maria Konieczny

In the Search for New Anticancer Drugs, I Antitumor Activity of Various Nitroxyl- and Aziridine-Containing Phosphorus Compounds

Abstract A series of pentavalent phosphorus compounds containing the nitroxyl and/or aziridinyl moieties was evaluated for antitumor activity against P 388 and L 1210 lymphocytic leukemias, and compared to the clinical agent thio-TEPA (1). The compounds with the structures 5-13 were found to be active, with a T/C value greater than 125. The percent ILS was also determined.

Reaction of Trivalent Organophosphorus Compounds with Selenium

Selenium derivatives of pentavalent organophosphorus compounds 9, 10, 11 (Ṙ = 2,2,6,6- tetramethyl-1-oxyl-4-piperidyl), 12 and 13 were prepared in 79-99% yields via the reaction of the corresponding trivalent phosphorus compounds 14, 15, 16, 17, 18 with black selenium in benzene at room temperature in 20 hours.

Utilization of the Sterically Hindered Base, 4-Hydroxy-2,2,6,6-tetramethylpiperidine, as a Hydrogen Halide Acceptor

The synthetic utility of the sterically hindered base, 4-hydroxy-2,2,6,6-tetramethylpiperidine (1) as a hydrogen halide acceptor was studied. It was shown that base 1 can be effectively used in the quaternization reaction of primary aliphatic and aromatic amines to give the corresponding trimethylammonium iodides 2 in 88-98% yield. Base 1 was used also as the dehydrobrominating agent of alkyl and cycloalkyl bromides to give the corresponding unsaturated compounds in 82-95% yield.

In the Search for New Anticancer Drugs, V+ Study of the Binding of Spin-Labeled Thio-TEPA to Cells

Abstract The spin labeled analog, SL-O-TT (2), of Thio-TEPA (1) inhibits the incorporation of 3H-thymidine by 50% (IC50) at a dose of 2.6 × 10-4 M in L 1210 and at a dose of 6 × 10-4 M in P 388 murine leukemias. On the basis of cell fractionation studies, compound 2 was found to bind about qeually to the cell nuclei, microsomes, and mitochondria. ESR experiments indicate different of immobilization of the label in various fractions. The efficiency of binding of 2 to cells appears to be at least 6%.

In the search for new anticancer drugs. IV: Antitumor activity of seleno-TEPA

Abstract In order to test the effect of selenium on the anticancer activity of alkylating drugs, Seleno-TEPA (4), the selenium analog of the clinically used Thio-TEPA (1) was tested in vivo against the lymphocytic P 388 and lymphoid L1210 murine leukemias. Compound 4 is more active against P 388 leukemia than against L1210, and appears to be active over a narrower concentration range than Thio-TEPA (1). Compound 4 is less active against P 388 leukemia than 1, as evidenced by the T/C values of 164 for 4 and 239 for 1 at a dose of 4.2 mg/kg. The activity of 4 was also evaluated on the HL60 and K 562 human cell lines. Under the conditions of the cell colony assay technique, Seleno-TEPA (4) is less effective than Thio-TEPA (1).

In the Search for New Anticancer Drugs, II1 Antitumor Activity, Toxicity and Electron Spin Resonance of Spin Labeled Thio-TEPA Derivatives

The spin labeled analog of Thio-Tepa, 1-oxyl-2,2,6,6-tetramethyl-4-piperidyl-N,N;N′,N′−bis (ethylene)−phosphorodiamidothioate (SL−O−TT), which contains a nitroxyl free radical linked by an oxygen bridge to phosphorus, has antitumor properties against P388 murine leukemia (T/C = 242) and a higher therapeutic ratio (5.15) than its parent compound, Thio-TEPA (2.75). The drug is less toxic to P388 cells in culture as judged by the 3H-thymidine uptake. On the basis of electron spin resonance spectroscopy using L1210 cells incubated with SL−O−TT, it is concluded that the drug is bound to cells in culture in such a way as to restrict the motion of the nitroxyl label. A second spin labeled analog, 1-oxyl-2,2,6,6-tetramethyl-4-amino-piperidyl-N,N;N′,N′−bis (ethylene)−phosphorodiamidothioate (SL−NH−TT), containing a nitroxyl label linked by a nitrogen bridge to phosphorus, first synthesized by Russian workers, was prepared by an improved procedure in 95% yield. In vivo results indicate that this analog has about the same therapeutic value (2.73) as Thio-TEPA (2.75), and that higher doses of this compound are required than those for both the O-bridged analog and Thio-TEPA to achieve maximum T/C values.

Utilization of Various Phosphoryl Halides and Imidazolides for the Conversion of Aldoximes to Nitriles

Imidazolides of phosphorus 7, 9, and 13 are, in most cases, superior to the chloridates 4, 5 (Ṙ = 2,2,6,6-tetramethyl-1-oxyl-4-piperidyl), 6, 8, and 12 for the transformation of aliphatic and aromatic aldoximes to nitriles in yields generally exceeding 80%. The transformation is thought to occur via a phosphorylated intermediate, which was isolated in the case of the reaction bfn-butyraldoxime with the nitroxyl radical-labeled chloridate 4.

Novel Aspects in the Preparation of Phorone

Abstract The condensation of acetone using anhydrous hydrogen chloride results after three weeks at room temperature, in a 15% yield of phorone (4) and a 75% yield of mesityl oxide (5). In the presence of one weight percent of the Lewis acid, aluminium chloride, the yield of 4 is increased to 39%. An increase in the amount of the Lewis acid, aluminium chloride, to ten weight percent results in a 22% yield of phorone (4) and a 68% yield of mesityl oxide (5). In the presence of one hundred weight percent of aluminium chloride, in the absence of hydrogen chloride, the condensation produces a 62% yield of mesityl oxide (5) and no phorone (4). In the course of this investigation, two intermediates, 6 and 7 were isolated and characterized for the first time. These intermediates are the actual products formed in the condensation of acetone with hydrogen chloride, and not the “free” phorone (4) and mesityl oxide (5). The conversion of 6 and 7 to 5 and 4, respectively, occurs during the isolation stage using a saturated solution of ethanolic potassium hydroxide.

A Novel Approach to the Transformation of Aldoximes to Nitriles Utilizing Spin-Labeled Phosphoryl Imidazolides

The spin-labeled imidazolides of phosphorus 1 and 3 were utilized for the conversion of [xxx] aldoximes to nitriles in high yield. It is hypothesized that this transformation under mild, neutral conditions might serve as a model reaction, mimicking the detoxification of phosphorus-inhibited acetyl cholinesterases.

Transphosphorylative Spin-Labeling Utilizing Diimidazolides of Pentavalent Phosphorus

The reaction of the spin-labeled diimidazolide 1 with hydroxy and amino compounds was studied. Diimidazolide 1 was superior to the dichloridate 6 for the preparation of spinlabeled phosphates 3 and phosphorodiamidates 2. The spin-labeled phosphate 15 was synthesized through hydrolysis of 6. Spin-labeled cyclophosphoramidates (10-13), analogs of the cytotoxic Endoxan, were prepared by the reaction of 1 and 6 with the appropriate difunctional nucleophile. Inductive effects of substituents in the imidazolyl moiety on the transphosphorylation reaction were also studied. [xxx]